Donanemab Analyses Suggest Benefits for Select Alzheimer’s Patients

Baseline amyloid levels predicted amyloid plaque response with donanemab, an investigational drug targeting N-terminal pyroglutamate beta-amyloid in early Alzheimer’s disease, a post hoc review of phase II TRAILBLAZER-ALZ data found.

The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (r −0.54, P<0.001). On average, people with a greater baseline amyloid plaque level had greater amyloid plaque removal.

Clearing amyloid plaques with donanemab was associated with less clinical decline, but exploratory analyses indicated the benefit may emerge only in certain patients, reported John Sims, MD, and co-authors, all employees of drug developer Eli Lilly in Indianapolis, writing in JAMA Neurology.

A disease-progression model showed a significant association between the percentage of amyloid reduction and changes on the integrated Alzheimer Disease Rating Scale (iARDS) in people who carried an APOE4 risk allele, but not in others.

Modeling also suggested a hypothesis that amyloid plaques might remain below the amyloid-positivity threshold for about 4 years after discontinuing donanemab. No substantial treatment effect on global tau load emerged, but neocortical and regional standardized uptake value ratios showed donanemab slowed tau accumulation in a region-dependent manner.

“These results underscore the importance of amyloid plaques in Alzheimer’s disease and understanding amyloid status for treatment decisions,” Sims and colleagues wrote.

The findings “predict that those with lower baseline amyloid levels are more likely to be able to stop donanemab treatment sooner,” they added. “Once complete amyloid clearance was achieved and participants switched to placebo infusions, plaques did not regrow substantially over 1 year without treatment.”

The previously reported TRAILBLAZER-ALZ study of 257 early symptomatic Alzheimer’s patients — 131 randomly assigned to donanemab and 126 to placebo — showed donanemab met its primary endpoint on the iADRS, a composite measure developed by Lilly that combines the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL).

Baseline iADRS scores in TRAILBLAZER-ALZ were 106 out of a possible 144 in both groups (lower values indicate greater cognitive and functional impairment). Change from baseline at 76 weeks was −6.86 with donanemab and −10.06 with placebo, a difference of 3.20 points (95% CI 0.12-6.27, P=0.04).

In TRAILBLAZER-ALZ, overall reductions in amyloid plaque levels and global tau load on PET were 85.06 centiloids greater and 0.01 greater, respectively, with donanemab than with placebo at 76 weeks. Participants were considered to achieve complete plaque clearance if their post-treatment amyloid level was below 24.1 centiloids, the same threshold consistent with an Alzheimer’s disease diagnosis.

Almost three-quarters of study participants carried APOE4. Amyloid-related cerebral edema or effusions, mostly asymptomatic, occurred in 26.7% of the donanemab group and 0.8% of the placebo group.

Using correlations, regressions, and modeling to examine possible relationships between amyloid reduction and either tau pathology or clinical outcomes, post-hoc analyses suggested:

• Once it reached 11 centiloids or less, amyloid might not re-accumulate to the 24.1-centiloid level for 3.9 years (95% prediction interval, 1.9-8.3 years) after stopping treatment.
• Participants with complete plaque clearance at 24 weeks showed a greater slowing of tau accumulation over 18 months than those who didn’t reach the 24.1 centiloid threshold by that point.
• Relationships between amyloid reduction and iADRS scores were significant in APOE4 carriers, but not in participants without APOE4, which may be due to the relatively few noncarriers in TRAILBLAZER-ALZ or pharmacogenomic differences in treatment response, the researchers noted.

Interpretation of these exploratory analyses should be with caution, Sims and co-authors warned. The results did not control for multiplicity, and inflated type I error likely exists, they acknowledged. Ongoing donanemab trials — TRAILBLAZER-EXT, TRAILBLAZER-ALZ2, and TRAILBLAZER-ALZ4 — may confirm findings.

Lilly initiated a submission for donanemab for accelerated approval. The FDA accepted donanemab for priority review, the drug maker announced in August.